Phospholipase A2 of peroxiredoxin 6 has a critical role in tumor necrosis factor-induced apoptosis

Sy, Kim; Chun, Eunyoung; Ky, Lee

doi:10.1038/cdd.2011.21

Cited by 49 publications

(44 citation statements)

References 37 publications

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“…Prdx6 prevented hyperglycemiamediated apoptosis in lens epithelial cells (137) and decreased apoptosis in tumors could support an increased rate of tumor growth. However, to the contrary, Prdx6 supported, rather than inhibited, TNFα-mediated apoptosis in hepatocellular carcinoma cells in vitro, and also in primary bronchial epithelial cells and a gastric cell line (123,128,138). This latter effect would tend to dampen rather than increase tumor growth and invasiveness as observed for Prdx6…”

Section: Cancer and Carcinogenesismentioning

confidence: 85%

The phospholipase A2 activity of peroxiredoxin 6 [S]

Fisher

2018

Journal of Lipid Research

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Peroxiredoxin 6 (Prdx6) is a Ca 2+ -independent intracellular phospholipase A 2 (called aiPLA 2 )that is localized to cytosol, lysosomes, and lysosomal-related organelles. Activity is minimal at cytosolic pH but is increased significantly with enzyme phosphorylation, at acidic pH, and in the presence of oxidized phospholipid substrate; maximal activity with phosphorylated aiPLA 2 is ~2 µmol/min/mg protein. Prdx6 is a "moonlighting" protein that also expresses glutathione peroxidase and lysophosphatidylcholine acyl transferase activities.The catalytic site for aiPLA 2 activity is an S32-H26-D140 triad; S32-H26 is also the phospholipid binding site. Activity is inhibited by a serine "protease" inhibitor (diethyl p-nitrophenyl phosphate),an analogue of the PLA 2 transition state (1-hexadecyl-3-(trifluoroethyl)-sn-glycero-2-phosphomethanol, MJ33), and by two naturally occurring proteins (surfactant protein A and p67 phox ), but not by bromoenol lactone. aiPLA 2 activity has important physiological roles in the turnover (synthesis and degradation) of lung surfactant phospholipids, in the repair of peroxidized cell membranes, and in the activation of NADPH oxidase (NOX2). The enzyme has been implicated in acute lung injury, carcinogenesis, neurodegenerative diseases, diabetes, male infertility, and sundry other conditions although its specific roles have not been well defined. Protein mutations and animal models are now available to further investigate the roles of Prdx6-aiPLA 2 activity in normal and pathological physiology.

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Section: Cancer and Carcinogenesismentioning

confidence: 85%

The phospholipase A2 activity of peroxiredoxin 6 [S]

Fisher

2018

Journal of Lipid Research

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“…The interaction was detected by Western blotting with anti-Myc antibody. The presence of Myc-TAK1, Flag-S6K1, or Flag-S6K1 truncated mutants in the pre-IP lysates was verified by Western blotting (12)(13)(14).…”

mentioning

confidence: 99%

S6K1 Negatively Regulates TAK1 Activity in the Toll-Like Receptor Signaling Pathway

Kim

Baik

Baek

et al. 2014

Molecular and Cellular Biology

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dTransforming growth factor ␤ (TGF-␤)-activated kinase 1 (TAK1) is a key regulator in the signals transduced by proinflammatory cytokines and Toll-like receptors (TLRs). The regulatory mechanism of TAK1 in response to various tissue types and stimuli remains incompletely understood. Here, we show that ribosomal S6 kinase 1 (S6K1) negatively regulates TLR-mediated signals by inhibiting TAK1 activity. S6K1 overexpression causes a marked reduction in NF-B and AP-1 activity induced by stimulation of TLR2 or TLR4. In contrast, S6K1؊/؊ and S6K1 knockdown cells display enhanced production of inflammatory cytokines. Moreover, S6K1؊/؊ mice exhibit decreased survival in response to challenge with lipopolysaccharide (LPS). We found that S6K1 inhibits TAK1 kinase activity by interfering with the interaction between TAK1 and TAB1, which is a key regulator protein for TAK1 catalytic function. Upon stimulation with TLR ligands, S6K1 deficiency causes a marked increase in TAK1 kinase activity that in turn induces a substantial enhancement of NF-B-dependent gene expression, indicating that S6K1 is negatively involved in the TLR signaling pathway by the inhibition of TAK1 activity. Our findings contribute to understanding the molecular pathogenesis of the impaired immune responses seen in type 2 diabetes, where S6K1 plays a key role both in driving insulin resistance and modulating TLR signaling.T ransforming growth factor ␤-activated kinase 1 (TAK1) is a member of the mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) family (1). TAK1 is essential for the production of tumor necrosis factor (TNF-␣) and other inflammatory mediators by activating several MAPKs, such as p38␣ MAPK, Jun N-terminal protein kinases 1 and 2 (JNK1 and JNK2), and extracellular signal-regulated kinases 1 and 2 (ERK1/2). TAK1 also plays a key regulatory role in several cytokine-mediated innate immunity signal transduction cascades, including interleukin-1 (IL-1) and the downstream signaling of Toll-like receptors (TLRs) and NOD1/2 (2, 3). In these pathways, various proinflammatory cytokines and TLR agonists trigger TAK1 activity, leading to its autophosphorylation and subsequent recruitment to the IB kinase (IKK) complex, ultimately resulting in the activation of the transcription factor NF-B and the upregulation of genes encoding proinflammatory cytokines, chemokines, adhesion molecules, and proteolytic enzymes.Several binding partners of TAK1, including TAK1-binding protein 1 (TAB1), TAB2, and TAB3, have been implicated in the regulation of TAK1 activity in response to various stimuli (1, 4). Previous reports demonstrated that the native forms of TAK1 comprise a catalytic kinase subunit in complex with the regulatory subunit TAB1 and either of two homologous proteins, TAB2 and TAB3 (2, 5, 6). Importantly, it has been reported that TAB1 might play a key role in the regulation of the TAK1 complex (7,8). Studies with TAB1-deficient mouse embryonic fibroblasts (TAB1 Ϫ/Ϫ MEFs) demonstrated that TAB1 is able to recruit p38␣ MAPK to the TAK1 complex f...

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“…While we found that the absence of Prdx6 does not affect bacterial numbers following respiratory infection, it is possible that Prdx6 may influence the innate immune response to Y. pestis in the lungs (11,53). Therefore, to test the impact of Prdx6 deficiency on the host response, we first examined the pulmonary pathology of Prdx6-deficient mouse lungs at 48 h postinfection following i.n.…”

Section: Identification Of Pla Substrates Within Mouse Balfmentioning

confidence: 99%

Inactivation of Peroxiredoxin 6 by the Pla Protease of Yersinia pestis

et al. 2016

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Pneumonic plague represents the most severe form of disease caused by Yersinia pestis due to its ease of transmission, rapid progression, and high mortality rate. The Y. pestis outer membrane Pla protease is essential for the development of pneumonic plague; however, the complete repertoire of substrates cleaved by Pla in the lungs is not known. In this study, we describe a proteomic screen to identify host proteins contained within the bronchoalveolar lavage fluid of mice that are cleaved and/or processed by Y. pestis in a Pla-dependent manner. We identified peroxiredoxin 6 (Prdx6), a host factor that contributes to pulmonary surfactant metabolism and lung defense against oxidative stress, as a previously unknown substrate of Pla. Pla cleaves Prdx6 at three distinct sites, and these cleavages disrupt both the peroxidase and phospholipase A 2 activities of Prdx6. In addition, we found that infection with wild-type Y. pestis reduces the abundance of extracellular Prdx6 in the lungs compared to that after infection with ⌬pla Y. pestis, suggesting that Pla cleaves Prdx6 in the pulmonary compartment. However, following infection with either wild-type or ⌬pla Y. pestis, Prdx6-deficient mice exhibit no differences in bacterial burden, host immune response, or lung damage from wild-type mice. Thus, while Pla is able to disrupt Prdx6 function in vitro and reduce Prdx6 levels in vivo, the cleavage of Prdx6 has little detectable impact on the progression or outcome of pneumonic plague.

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Phospholipase A2 of peroxiredoxin 6 has a critical role in tumor necrosis factor-induced apoptosis

Cited by 49 publications

References 37 publications

The phospholipase A2 activity of peroxiredoxin 6 [S]

The phospholipase A2 activity of peroxiredoxin 6 [S]

S6K1 Negatively Regulates TAK1 Activity in the Toll-Like Receptor Signaling Pathway

Inactivation of Peroxiredoxin 6 by the Pla Protease of Yersinia pestis

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